The present invention, in some embodiments thereof, relates to the field of pharmacology and, more particularly, but not exclusively, to heterocyclic compounds and their use in the treatment of sexual disorders such as decreased libido, orgasm disorder and erectile dysfunction. The present invention, in some embodiments thereof, relates to novel heterocyclic compounds, to heterocyclic compounds which exhibit substantial activity in treating sexual disorders in female, and/or to novel regimens for treating sexual disorders while utilizing the described heterocyclic compounds.
Selective inhibitors of PDE5 (phosphodiesterase-5) are used for inducing penile erection by raising cGMP levels (Terret et al., 1996). PDE5 hydrolyses cGMP (cyclic guanosine monophosphate), and is located prominently in the penis. Inhibition of PDE5 results in higher cGMP levels in the penis. The cGMP mediates erection by inducing relaxation of the arterial smooth muscle, thereby increasing the volume of blood flowing through the arteries. The increased volume of blood entering the penis leads to an erection.
Male patients suffering from erectile dysfunction generally respond well to medications of the PDE5 inhibitor family, with approximately 80% success rates (Evans et al., 1980; Hyttel, 1982). The principal currently available drugs belonging to the PDE5 inhibitor family are tadalafil (Cialis™), vardenafil (Levitra™) and sildenafil (Viagra™) the most famous one being Viagra™ (sildenafil).
While sildenafil is considered a selective inhibitor of PDE5, it has long been recognized that it effects on other body organs and hence its use is associated with several adverse side effects such as nausea, headache, and cutaneous flushing. These clinically significant adverse effects are thought to be due to nonspecific inhibition of other PDEs exhibited by this compound (Beavo, 1998; Moreland and Goldstein, 1995).
Although clitoral erection in women is caused by an analogous mechanism to that of penile erection, PDE5 inhibitors have had little success in treating sexual dysfunction in women.
In addition to PDE5, experimental data indicate that several neurotransmitters and neuropeptides in the central nervous system are involved in the control of penile erection and sexual behavior, one such prominent neurotransmitter being dopamine (Melis and Argiolas, 1995; Andersson, 2001). In contrast to PDE5 inhibition, which directly affects the blood vessels in the penis, dopamine is involved in the regulation of penile activity by the central nervous system.
Dopamine is one of the key mediators in the CNS and is involved in a variety of physiological functions, including sexual behavior, cognition, motor coordination, cardiovascular control, reward and hormonal regulation. It has been shown that several dopamine receptor agonists such as apomorphine, quinpirole, quinelorane, PIP3EA, and (−)-3-(3-hydroxyphenyl)-N-n-propylpiperidine (3-PPP) induce penile erection after systemic administration in mammals (Melis and Argiolas, 1995; Enguehard-Gueffier et al. 2006).
Apomorphine induces erection by activating the D4 receptor, although other dopamine receptors may also be involved (Brioni et al., 2004). U.S. Pat. No. 5,945,117 describes amelioration of female sexual dysfunction by sublingual administration of apomorphine.
However, apomorphine is classified as a nonselective agonist because it activates all of the dopamine receptor subtypes (Missale, 1998). It is believed that such non-selectivity is associated with the known emetic action that substantially restricts the practical application of apomorphine.
ABT-724 (2-[(4-pyridin-2-ylpiperazin-1-yl)methyl]-1H-benzimidazole) is a selective D4 agonist (Brioni et al., 2004). Methods of using ABT-724 and related compounds in the treatment of various sexual dysfunctions are disclosed in U.S. Pat. Nos. 7,022,728 and 6,960,589, to Cowart et al.
PIP3EA is a selective D4 agonist, and induces penile erection via D4 activation (Enguehard-Gueffier et al. 2006).
Other highly selective dopamine receptor D4 agonists have also been developed. These include, for example, PD-168077 (Melis et al., 2006), A-412997 (Moreland et al., 2005) and A-381393 (Nakane et al., 2005).
U.S. Pat. No. 7,115,103 describes the use of flibanserin, which binds to serotonin receptors, for treating disorders of sexual desire.
International Patent Application PCT/IL2007/000404 (published as WO 2007/110868) describe heterocyclic compounds which exhibit a dopamine receptor (e.g., D4 receptor) agonist activity and/or a PDES inhibitory activity, for use in the treatment of sexual disorders such as decreased libido, orgasm disorder and erectile dysfunction.